The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

Feldman, Douglas E.; Chauhan, Vibha; Koong, Albert C.

doi:10.1158/1541-7786.mcr-05-0221

Cited by 278 publications

(233 citation statements)

References 101 publications

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“…We found that phosphorylation of eIF2a also occurs in response to more moderate hypoxia (0.2% and 1% oxygen) but requires significantly longer hypoxic exposures (>8 hours). Several additional reports have confirmed the increase in eIF2a phosphorylation during both severe and moderate hypoxic exposures (27)(28)(29).…”

Section: Perk-eukaryotic Initiation Factor 2a Control Of Translation mentioning

confidence: 79%

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

Koumenis

Wouters

2006

Molecular Cancer Research

210

170

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Poor oxygenation (hypoxia) is present in the majority of human tumors and is associated with poor prognosis due to the protection it affords to radiotherapy and chemotherapy. Hypoxia also elicits multiple cellular response pathways that alter gene expression and affect tumor progression, including two recently identified separate pathways that strongly suppress the rates of mRNA translation during hypoxia. The first pathway is activated extremely rapidly and is mediated by phosphorylation and inhibition of the eukaryotic initiation factor 2A. Phosphorylation of this factor occurs as part of a coordinated endoplasmic reticulum stress response program known as the unfolded protein response and activation of this program is required for hypoxic cell survival and tumor growth. Translation during hypoxia is also inhibited through the inactivation of a second eukaryotic initiation complex, eukaryotic initiation factor 4F. At least part of this inhibition is mediated through a Redd1 and tuberous sclerosis complex 1/2 -dependent inhibition of the mammalian target of rapamycin kinase. Inhibition of mRNA translation is hypothesized to affect the cellular tolerance to hypoxia in part by promoting energy homeostasis. However, regulation of translation also results in a specific increase in the synthesis of a subset of hypoxia-induced proteins. Consequently, both arms of translational control during hypoxia influence gene expression and phenotype. These hypoxic response pathways show differential activation requirements that are dependent on the level of oxygenation and duration of hypoxia and are themselves highly dynamic. Thus, the severity and duration of hypoxia can lead to different biological and therapeutic consequences. (Mol Cancer Res 2006;4(7):423 -36)

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Section: Perk-eukaryotic Initiation Factor 2a Control Of Translation mentioning

confidence: 79%

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

Koumenis

Wouters

2006

Molecular Cancer Research

210

170

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“…The accumulation of misfolded proteins disturbs cellular redox regulation and stimulates the production of endogenous ROS [27], leading to the activation of ER stress signals and ER dysfunction. In response to increased ROS levels, the ER elicits a series of effector signals known as the UPR to adapt to the changing environment and restore ER function and homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress

et al. 2016

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Parkinson's disease (PD) is a neurodegenerative disease characterized by a persistent decline of dopaminergic (DA) neurons in the substantia nigra pars compacta. Despite its frequency, effective therapeutic strategies that halt the neurodegenerative processes are lacking, reinforcing the need to better understand the molecular drivers of this disease. Importantly, increasing evidence suggests that the endoplasmic reticulum (ER) stress-induced unfolded protein response is likely involved in DA neuronal death. Salidroside, a major compound isolated from Rhodiola rosea L., possesses potent antioxidative stress properties and protects against DA neuronal death. However, the underlying mechanisms are not well understood. In the present study, we demonstrate that salidroside prevents 6-hydroxydopamine (6-OHDA)-induced cytotoxicity by attenuating ER stress. Furthermore, treatment of a DA neuronal cell line (SN4741) and primary cortical neurons with salidroside significantly reduced neurotoxin-induced increases in cytoplasmic reactive oxygen species and calcium, both of which cause ER stress, and cleaved caspase-12, which is responsible for ER stress-induced cell death. Together, these results suggest that salidroside protects SN4741 cells and primary cortical neurons from 6-OHDA-induced neurotoxicity by attenuating ER stress. This provides a rationale for the investigation of salidroside as a potential therapeutic agent in animal models of PD.

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“…It activates a subsequent mechanism to promote cellular proliferation and blocks programmed cell death. 29,30 Malignant cells are permanently exposed to stress, mainly induced by hypoxic conditions and glucose deprivation caused by poor vascularization in their metabolic microenvironment, 35,36 and to immunological attacks. 37,38 For their survival, they have to adapt their cellular turnover to a higher need of nutrition and energy.…”

Section: Discussionmentioning

confidence: 99%

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Rauschert

Brändlein

Holzinger

et al. 2008

Laboratory Investigation

121

104

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The chaperone GRP78 is a member of the heat-shock protein 70 (HSP70) family and is responsible for cellular homeostasis by preventing stress-induced apoptosis. GRP78 is expressed in all cells of the body. In malignant cells, which are permanently exposed to environmental stress, GRP78 is overexpressed and increased levels can be found in the cytoplasm and on the cell membrane. Thus, GRP78 promotes tumor proliferation, survival, metastases and resistance to a wide variety of therapies. Like other tumor-specific membrane molecules, GRP78 can also be present on cancer cells in a variant form. This modification qualifies it as a target for immune surveillance and antibody responses. The fully human monoclonal IgM antibody, SAM-6, was isolated from a gastric cancer patient and it binds to a new variant of GRP78 with a molecular weight of 82 kDa. The epitope is an O-linked carbohydrate moiety and is specific for malignant cells. These data show that cancer-specific modifications of cell-surface protection molecules are (a) subject of an immune response and (b) ideal targets for new therapeutical approaches.

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The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

Cited by 278 publications

References 101 publications

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress

A new tumor-specific variant of GRP78 as target for antibody-based therapy

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